Agents for diagnosing and treating melanomas, aromatic halogenated derivatives usable as such agents and their preparation

ABSTRACT

##STR1## The invention concerns agents for diagnosing and treating malignant melanomas, of general formula (I), in which X denotes a hydrogen or halogen atom, Y denotes a Z--CONH--, Z--O--, Z--S(O)-- n1  group, n 1  being equal to 0,1,2 or 3, a Z--SO 2  --NH-- Z--NHCO-- group, Z being a bond, a --CH 2  -- or --CH(C 6  H 5 )-- group, n is an integer between 2 and 4, and R 1  and R 2  each denote a hydrogen atom, a C 1  to C 6  alkyl group or a C 6  to C 12  aryl or aralkyl group, these compounds possibly being labelled by radioisotopes chosen from  123  I,  123  I,  123  I,  75  Br,  77  Br,  18  F, or  11  C or by stable isotopes chosen from  13  C and  19  F, as well as their addition salts with pharmaceutically acceptable acids. The invention also concerns the use of these compounds to manufacture an agent for diagnosing and/or treating malignant melanomas.

The present invention concerns agents for diagnosing and treating malignant melanomas and novel, optionally labelled aromatic halogenated derivatives usable as such agents.

The malignant melanoma is one of the most dangerous tumors of the skin with a regularly increasing incidence. Survival for 5 years does not exceed 14% except in the case in which the thickness of the tumor is less than 0.76 mm. In the case in which the lesion exceeds this thickness, the tumor gives rise to metastases in a silent and unpredictable manner. That is why a method of investigation is presently being sought which makes possible an early evaluation of both the local extension and extension at a distance of the tumor.

During the last ten years, a number of radiopharmaceutical products, selected for their potential affinity for melanin, have been tested but few have had a satisfactory clinical development. We will mention only the iodoquinolines and the iodomethyltyrosines, which have today been abandoned and the citrate of gallium 67, the disadvantages of which are well-known: very slow elimination from the digestive tract, late and extensive localization in the liver and the kidney which can make the visualization of the tumor difficult. Moreover, the labelling occurs non specifically at infectious or inflammatory foci or the developing tumoral tissue.

Many attempts have been made to show the usefulness of monoclonal antibodies for the immunoscanning of tumors. The first attempts were made with a monoclonal antibody labelled with ¹³¹ I directed against the protein p 97 present in the majority of the cells of human melanoma. Experiments in animals, followed by clinical study, have shown the superiority of the use of an antibody directed against a fragment of the p 97 protein, F (a b')2 compared with the antibody directed against the complete protein for carrying out the immunoscannings. These antibodies make it possible to detect melanomas of a size greater than 1.5 cm but the sensitivity is affected by the anatomical site of the tumors and by their antigen content. The major limitation of immunoscanning resides in the non-specific accumulation of radio-activity in the bone marrow, the spleen, the liver and the kidney. It appears imperative to improve either the labelling and/or the purification of the antibody in order to reduce the renal and hepatic activities.

More recently, iodothiouracil labelled with ¹²⁵ I has been studied in animals bearing grafted tumors. It seems to be a promising agent for the localization and the treatment of malignant melanoma: however, the labelling of this compound by total synthesis is still not suited to the use of ¹²³ I. Moreover, its incorporation as pseudoprecursor of melanin during the process of biosynthesis may limit its use. Preliminary studies carried out with porphyrins labelled with ¹¹¹ In have made it possible to detect grafted tumors in animals. Finally, ¹²³ I-IMP has been used for the detection of melanoma in man. A comparative study with the anti-melanoma monoclonal antibodies labelled with ¹¹¹ In has shown a higher sensitivity of the immunoscanning.

From another point of view, the present authors have described benzene compounds labelled with ¹²⁵ I, usable in nuclear medicine for the exploration of the central nervous system (Eur. J. Med. Chem.-Chim. Ther. 1986, 21, No. 5, 423-31).

It has now been found that these compounds as well as novel compounds of analogous structure may be used as tracers of melanomas.

Thus, the object of the present invention is agents for diagnosing and treating malignant melanomas, corresponding to the general formula ##STR2## in which X represents a hydrogen or halogen atom,

Y represents a Z--CONH--, Z--O--, Z--S(O)--_(n1) group with n₁ =0,1,2 or 3, Z--SO₂ --NH-- or Z--NHCO-- group, Z being a bond, --CH₂ -- or ##STR3## n is an integer from 2 to 4, and R₁ and R₂ each represents a hydrogen atom, a C₁ -C₆ alkyl, aryl or C₆ -C₁₂ aralkyl group,

these compounds being labelled with radioisotopes selected from ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁷ Br, ¹⁸ F, or ¹¹ C, or stable isotopes selected from ¹³ C and ¹⁹ F, as well as their addition salts with pharmaceutically acceptable acids, with the exclusion of the compounds of formula I in which Y represents Z--CONH--, Z being a bond and X represents F, Cl, Br in the ortho, meta or para position or I in the ortho or meta position, compounds of formula I in which Y represents Z--SO₂ --NH--, Z being a bond and X represents Cl in the para position and the compound of formula I in which Y represents Z--CO--NH--, Z being a bond, X is an iodine atom in the para position and R₁ and R₂ represent an ethyl group.

The invention relates more particularly to the radiopharmaceutical agents of formula I in which X represents ¹²³ I, ¹²⁵ I or ¹³¹ I, Y represents Z--CONH-- or Z--SO₂ NH--, Z being a bond, --CH₂ -- or ##STR4## R₁ and R₂ each represents a hydrogen atom or a C₁ -C₆ alkyl group.

Of these agents (I), the compounds of the following general formula II are novel: ##STR5## in which X₁ represents a halogen atom or one of its radioisotopes,

Y₁ represents a CO or SO₂ group,

n is an integer from 2 to 4, and

R₁ and R₂ each represents a hydrogen atom or a C₁ -C₆ alkyl group,

as well as their addition salts with pharmaceutically acceptable acids with the exception of the compounds of formula II in which Y₁ represents CO, X₁ represents F, Cl, Br in the ortho, meta or para position of I in the ortho or meta position, compounds of formula II in which Y₁ represents SO₂ and X₁ represents Cl in the para position and the compound of formula II in which Y₁ represents CO, X₁ is an iodine atom in the para position and R₁ and R₂ represent an ethyl group.

The compounds of formula II may be prepared by condensation of a halogenobenzoic or halogenobenzenesulfonic acid chloride of formula ##STR6## in which X₁ and Y₁ have the same meaning as in formula II, with a diamine of formula

    NH.sub.2 --(CH.sub.2).sub.n --NR.sub.1 R.sub.2             IV

in which n, R₁ and R₁ have the same meaning as in formula II, then optional labelling of the structure (II) thus obtained with a radioisotope of the halogen X₁, in particular ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁷ Br or ¹⁸ F.

The condensation reaction between (III) and (IV) may be carried out at room temperature in a neutral solvent such as tetrahydrofuran (THF). The reaction is preferably carried out with an excess of diamine (IV), in particular about 2 moles of (IV) for one mole of (III).

The compounds of formula II in which Y₁ =CO may also be prepared by condensation of a halogenobenzoic acid chloride (III) with paranitrophenol in order to obtain an ester of formula: ##STR7## then reaction of compound (V) with a diamine (IV) and, finally, optional labelling of the structure (II) thus obtained by a radioisotope of X₁.

The condensation reaction of the acid (III) with paranitrophenol may be carried out at a temperature of 30° to 50° C. in a neutral solvent such as THF and in the presence of an acid acceptor (carbonate, amine).

The reaction between the compounds (V) and (IV) may be carried out at room temperature in a neutral solvent such as THF, preferably with an excess of diamine (IV), in particular about 2 moles of (IV) for one mole of (V).

The labelling of the structure (II) is carried out by exchange in an acidic medium between the non-radioactive iodinated molecule and a radioactive alkali halide, for example Na¹²⁵ I. The exchange may be carried out by refluxing an aqueous solution of the compound (II) and the radioactive halide, acidified for example by means of acetic acid in the presence of copper sulfate.

The following examples illustrate the invention.

EXAMPLE 1 N-(2-diethylaminoethyl) 4-iodo benzamide and its hydrochloride (compound A)

a) A solution of 20 mM of commercially available N,N-diethyl ethylenediamine is allowed to react overnight with 10 mM of paraiodobenzoic acid chloride (prepared from 10 mM of paraiodobenzoic acid and 10 mM of thionyl chloride) in 50 ml of THF. The solvent is evaporated, the residue is taken up in water and extracted with chloroform. The chloroform solution is dried over MgSO₄, then purified on a chromatography column (silica; eluant: CHCl₃ --5% to 20% EtOH gradient or CHCl₃ --EtOH--Et₂ NH 92% -6% - 2% v/v). Yield: about 80%.

Preparation of the Hydrochloride

Compound A, isolated in the form of the base, is dissolved in a minimum of chloroform and treated with HCl/ether (≃ 2N) until precipitation is complete. The mixture is evaporated in a vacuum and the hydrochloride form is washed with anhydrous ether and filtered off. M.p. 184°-185° C.

IR (KBr disk, ν cm⁻¹): 3220 (NH); 3030 (aromatic CH); 1970 (CH₃); 2930 (CH₂); 1635 (CO); 1575, 1520 (C-NH).

¹ H-NMR (solvent: methanol (D4): 1.35 (t, 6H, CH₃ ; 3.10-3.53 (m, 6H, CH₂ --N--(CH₂ CH₃)₂ --); 3.65-3.90 (m, 2H, CONH--CH₂); 7.46-7.93 (m, 4H, aromatics).

b) labelling with ¹²⁵ I

Method 1: Compound A (52 μM) in solution in 1 ml of water. Acetic acid: 250 μl. Copper sulfate: 80 μM. Na ¹²⁵ I. 45 mn at 170° C. Hydrolysis (N NaOH). Passage through "Extrelut" (chloroform elution). Evaporation. Treatment of the residue with HCl, ether. The product A is isolated in the form of the hydrochloride. Radiochemical yield: 95%. Radiochemical purity>98% (TLC, HPLC).

Method 2: Compound A (26 μM) in solution in 500 μl of 0.1M acetate buffer, pH 4.62. Copper sulfate: 1.26 μM. Na ¹²⁵ I. 45 mn at 120°. TLC, HPLC of the mixture--radiochemical purity>97.5% (loss of radioactivity observed<7%).

Method 3: Compound A (26 μM) in solution in 500 μl of 0.05M citrate buffer, pH 4. Copper sulfate: 3 μM. Na ¹²⁵ I. 35 mn at 150°. TLC, PHLC of the mixture--radiochemical purity>98% (loss of radioactivity observed<3%).

EXAMPLE 2 N-(2-ethylaminoethyl) 4-iodo benzamide and its hydrochloride (compound B)

a) p-nitrophenyl p-iodobenzoate

2 mM of p-nitrophenol are reacted overnight with 2 mM of p-iodo benzoic acid chloride in the presence of 2 mM of triethylamine in 20 ml of THF. The solvent is evaporated and the residue is taken up in chloroform and washed with 1N HCl, then with water. The solution is dried over MgSO₄. It is purified on a chromatography column (silica; eluant CHCl₃ -hexane 85/15 v/v). Yield: 90%.

b) the preceding ester (1 mM) is reacted with commercially available N-ethylethylenediamine (2 mM) in 20 ml of THF for 24 h at room temperature. The solvent is evaporated, the residue is taken up in water and extracted with chloroform. The organic phase is washed with 1N NaOH, then H₂ O. It is dried over MgSO₄. It is purified on a chromatography column (silica; eluant: CHCl₃ --EtOH--Et₂ NH 92%/6%/2% v/v). The hydrochloride of the title compound is prepared in the same manner as in example 1. M.p.=242°-243° C.

IR (KBr disk, cm⁻¹): 3280 (NH); 1635 (CO); 1575 (C--NH); 1540 (NH).

¹ H-NMR (solvent: DMSO D₆ +D₂ O+CF₃ COOH): 1.20 (t, 3H, CH₃); 2.83-3.27 (m, 4H, --CH₂ --NH--CH₂ --CH₃); 3.43-3.70 (m, 2H, CONH--CH₂); 7.50-7.93 (m, 4H, aromatics).

c) labelling with ¹²⁵ I

Method 1: The protocol used is the same as that described for compound A in example 1. Radiochemical yield: 90%. Radiochemical purity>98% (TLC, HPLC).

Method 2: Same protocol as in example 1. Radiochemical purity 97% (TLC).

These compounds as well as other derivatives of formula II prepared in a similar manner are presented in the following table:

                  TABLE                                                            ______________________________________                                         Derivative                                                                             X.sub.1  Y.sub.1 n    R.sub.1 R.sub.2                                  ______________________________________                                         A(*)    para-I   CO      2    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                          B       para-I   CO      2    H       C.sub.2 H.sub.5                          C       ortho-I  CO      2    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                          D       para-I   CO      2    H       H                                        E       para-I   CO      2    CH.sub.3                                                                               CH.sub.3                                 F       para-I   CO      2    H       CH.sub.3                                 G       para-I   CO      2    CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                       H       para-I   CO      2    H       CH(CH.sub.3).sub.2                       J       para-I   CO      3    CH.sub.3                                                                               CH.sub.3                                 K       para-I   CO      3    H       CH.sub.3                                 L       para-I   CO      3    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                          M       para-I   SO.sub.2                                                                               2    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                          ______________________________________                                          (*)described in Eur. J. Med. Chem. previously mentioned in No. 14.   The       melting points are taken on a Kofler block.

The ¹ H-NMR spectra are recorded on a JEOL C60 HL apparatus, the chemical shifts are expressed in ppm with respect to the TMS used as internal reference.

Compound C

M.p. (°C.)=169-170

¹ H-NMR (solvent: Methanol D₄): 1.40 (t, 6H, CH₃); 3.0-4.0 (m, 8H, CONH CH₂ CH₂ --N(CH₂ CH₃)₂ ; 7.07-7.63 (m, 3H, aromatics); 7.87-8.10 (m, 1H, aromatic).

Compound D

M.p. (°C.)>250

¹ H-NMR (solvent: Methanol D4); 3.03-3.43 (m, 2H, CH₂ NH₂); 3.53-3.83 (m, 2H, CONH CH₂); 7.50-7.93 (m, 4H, aromatics).

Compound E

M.p. (°C.)=240-241

¹ H-NMR (solvent: methanol D4): 3.0 (s, 6H, CH₃); 3.27-3.60 (m, 2H, CH₂ N(CH₃)₂); 3.67-4.0 (m, 2H, CONH CH₂); 7.53-8.07 (m, 4H, aromatics)

Compound F

M.p. (°C.)>250

¹ H-NMR (solvent: DMSO+D₂ O): 2.67 (s, 3H, CH₃); 3.03-3.33 (m, 2H, CH₂ --NH--CH₃); 3.50-3.77 (m, 2H, CONH CH₂); 7.53-8.0 (m, 4H, aromatics)

Compound G

M.p. (°C.)=185-186

¹ H-NMR (solvent: methanol D4): 1.37 and 1.47 (2s, 12H, CH₃); 3.23-4.0 (m, 6H, CH₂ and CH); 7.57-8.0 (m, 4H, aromatics)

Compound H

M.p. (°C.)=219-220

¹ H-NMR (solvent: methanol D4): 1.30 and 1.43 (2s, 6H, CH₃); 3.13-3.50 (m, 3H, CH₂ NH--CH (CH₃)₂); 3.57-3.90 (m, 2H, CONH CH₂); 7.50-7.93 (m, 4H, aromatics)

Compound J

M.p. (°C.)=165-166

¹ H-NMR (solvent: methanol D4): 1.77-2.33 (m, 2H, CH₂ --CH₂ --CH₂); 2.93 (s, 6H, CH₃); 3.0-3.67 (m, 4H, CONH, CH₂ CH₂ CH₂): 7.47-7.97 (m, 4H, aromatics)

Compound K

M.p. (°C.)=243-244

¹ H-NMR (solvent: methanol D4): 1.87-2.30 (m, 2H, CH₂ CH₂ CH₂); 2.73 (s, 3H, CH₃); 2.93-3.23 (m, 2H, CH₂ NH CH₃); 3.33-3.70 (m, 2H, CONH CH₂); 7.50-8.0 (m, 4H, aromatics)

Compound L

M.p. (°C.)=88-90

¹ H-NMR (solvent: methanol D4): 1.33 (t, 6H, CH₃); 1.93-2.40 (m, 2H, CONHCH₂ CH₂ CH₂); 3.03-3.70 (m, 8H, CONH CH₂ CH₂ CH₂ N(CH₂ CH₃)₂); 7.53-7.97 (m, 4H, aromatics)

Compound M

M.p. (°C.)=154-155

¹ H-NMR (solvent: methanol D4): 1.33 (t, 6H, CH₃); 3.0-3.53 (m, 8H, CH₂); 7.50-8.13 (m, 4H, aromatics)

The compounds of the invention were subjected to pharmacological and biological assays.

1. Toxicity Study

The determination of the LD50 is made in the mouse after i.v. injection of the molecules according to the methodology described by Karber and Behrens.

It was carried out in:

6 weeks old OF 1 male mice

6 weeks old male nu/nu SSCUP nude mice,

male nu/nu SSCUP nude mice bearing heterotransplants of human melanomas.

    ______________________________________                                         a. after the i.v. injection of the derivative  .sub.-- A.                      6 weeks old OF 1 male mice                                                            LD 0:         75 mg/kg                                                         LD 50:       125 mg/kg                                                         LD 100:      150 mg/kg                                                   6 weeks old male nu/nu SSCUP nude mice                                               LD 0:         60 mg/kg                                                         LD 50:        90 mg/kg                                                         LD 100:      150 mg/kg                                                  Male nu/nu SSCUP nude mice, bearing hetero-                                    transplants (Beu melanoma)                                                            LD 0:         60 mg/kg                                                         LD 50:        90 mg/kg                                                         LD 100:      150 mg/kg                                                  b. after the i.v. injection of derivative  .sub.-- B:                          6 weeks old OF 1 male mice                                                            LD 0:        150 mg/kg                                                         LD 50:       175 mg/kg                                                         LD 100:      200 mg/kg                                                  ______________________________________                                    

2. Autoradiograms

The autoradiograms are carried out in mice bearing grafted melanomas:

a. C57 BL6 bearing the B16 murine melanoma.

b. nu/nu SSCUP nudes bearing heterotransplants of melanic (Beu) or amelanic (Dau) human melanomas). The value of this model resides in the fact that these human tumors maintain their biochemical and histological properties.

The animals bearing grafted tumors receive the labelled compounds in the form of the hydrochloride in saline solution (3.7 to 5×10⁵ Bq/animal) in a caudal vein. At different time intervals after the administration of the compounds (from 15 minutes to 24 hours) the mice are anesthetized with ether and plunged into liquid nitrogen.

30 μm sections, parallel to a sagittal plane, are prepared in a freezing microtome (TS 260, SLEE) according to the protocol described by Ullberg. The sections, dehydrated in the cold, are applied to sensitive films, Ultrofim ³ H (LKB, 2208-190) or Hyperfilm ³ H (Amersham, RPN 535). After 3 weeks of exposure the films are revealed according to the standard methods of development.

c. Results.

A considerable and inhomogeneous darkening of the film can be seen at the level of the tumor from 1 to 4 h after the i.v. injection of ¹²⁵ I-A in C57 BL6 mice bearing the B16 melanoma. This heterogeneity corresponds to zones of necrosis of the tumor.

Identical images are obtained at the same times in nu/nu SSCUP nude mice bearing heterotransplants of melanic human melanoma, Beu. 24 h after the injection the B16 melanoma is still visible but we can no longer see darkening of the film at the site of the Beu tumor.

1 h after the injection of ¹²⁵ I-B into mice bearing the B16 melanoma, the darkening of the film at the site of the tumor is qualitatively as great as after the injection of A. The kinetics are slightly different with a more intense tumoral radioactive concentration at 4 h and particularly at 6 h. 24 hours after the injection the tumor is still visible although no radioactivity remains in the organism.

The heterotransplant Beu is visible up to 6 h after the injection and at this time shows a more pronounced darkening along the circumference of the tumor.

After the i.v. injection of B16 melanoma cells the appearance of predominantly pulmonary metastasing colonies is noticed. These pulmonary colonies are readily visualized on the autoradiograms from 1 to 7 hours after the injection of B.

3. Tissue Distribution in the Animal

The study of the tissue distribution of the ¹²⁵ I labelled compounds was performed in mice bearing grafted melanomas (cf. autoradiograms above).

The animals receive an injection of 3 μmoles, 13.5 to 29.6.10⁴ Bq of labelled compound in the form of the hydrochloride in a caudal vein. The animals are sacrificed at different time intervals of 1 to 24 hours after the injection. The blood is collected and the principal organs are excised. Aliquots are weighed and the radioactivity of the samples is measured in a Gammatrac 1191 counter (analytic tracer). The counting yield for iodine 125 is 60%.

Mice bearing melanomas

The results are expressed:

as a percentage of the injected dose bound per g of tissue (% ID/g);

in the form of the ratios ##EQU1##

This ratio reflects more precisely the selectivity of a molecule for an organ (tables 2, 4, 6, 8, 10 and 12).

Derivative A

Up to 8 hours after the injection of A into mice bearing melanic melanomas, B16 and Beu, intratumoral concentrations greater than 1% ID/g are noted with the values for B16 always being higher. Between 6 and 12 hours the tumor/blood ratios are of the order of 20 for the 2 tumors. Even though the ratio for B16 is higher than 30 24 h after the injection, that for Beu is only 6 (cf. tables 1 to 4 below).

The relatively marked pulmonary binding during the first 4 hours becomes less than 1% ID/g as from the 6th hour.

This study also makes it possible to observe that 6 hours after the injection the melanic melanomas are the tissues which show the highest percentages of binding and the highest tissue/blood ratios. The tumor/muscle, lung, brain and liver ratios, all very much greater than unity from 6 to 24 hours after the injection in mice bearing Beu or B16, are positive elements for a scanning study in the search for metastases.

In the case of the amelanic melanoma (Dau) the intratumoral concentration of A is only greater than 1% ID/g during the 2 hours which follow the injection. The tumor/blood ratios, which vary between 1 and 2 from 1 to 24 hours, have, however, enabled images to be obtained (cf. tables 5 and 6 below).

Derivative B

In the case of the melanic melanomas, the preliminary results show intratumoral concentrations and ratios markedly higher than those observed with A from 4 to 8 h after the injection. On the other hand, after 24 hours the concentrations and the tumor/blood ratios are lower than those of A (tables 7 and 8 below).

Furthermore, if an attempt is made to determine a contrast "index" of the melanic tumors with respect to the neighbouring muscles or organs likely to be the seat of metastases, it is possible to observe that at the time of 6 hours the majority of these indices are higher for B than for A, a result favouring the use of B for imaging at this time.

As far as the analysis of the results in the animals bearing the amelanic tumor is cocerned, the intratumoral concentrations are slightly higher from 4 to 6 h but the tumor/blood ratios are not significantly different (tables 9 and 10 below).

The derivatives E, G, J and L have also been studied. Like the derivatives A and B they are all markers of the B16 murine melanoma.

The derivative G shows elimination kinetics similar to those of derivative A, whereas the derivatives E, J and L show more rapid elimination. The derivative E shows possibilities for use in scanning between 3 h and 6 h after its administration.

4. Imaging

The mice bearing grafted tumors are anesthetized by the i.p. injection of sodium pentobarbital 1/5 and immobilized under a scintillation camera (Gammatome II, CGR) equipped with a pinhole 3-360 collimator, sensitivity 3.2 10⁻⁴. The images were obtained after the i.v. injection of 60 to 100 μCi of ¹²⁵ I and ¹²³ I-A into mice:

C57 BL6 bearing B16 melanomas at different stages of development.

C57 BL6 bearing pulmonary metastases of B16 melanoma. In fact, after the i.v. injection of B16 cells, the animal develops melanic pulmonary "colonies" similar to metastases.

nu/nu SSCUP nudes bearing human melanomas Beu and Dau.

nu/nu SSCUP nudes bearing FOSS(ORIS) melanic human melanoma.

In all of these human and murine models we have observed good tumoral definition. The early images are more difficult to interpret on account of considerable intraabdominal (digestive, renal and urinary) and pulmonary radioactivity. On the other hand, from the time of 4 h the tumor images are of good quality. It is to be noted that the intratumoral necrosis zones are not visualized. We have been able to obtain images of human melanoma less than 5 mm.

As far as the study of specificity is concerned we have not obtained any image after the injection of A to the following mice:

BALB bearing the EMT6 tumor (spontaneous mammary carcinoma of mice)

nu/nu SSCUP nudes bearing heterotransplants: SW 948 (adenocarcinoma of the colon) and A 431 (tumor of the vulva).

A study performed with ¹²³ I-A has made it possible to confirm the data obtained by imaging after the injection of ¹²⁵ I-A. In fact we have been able to observe identical images in mice bearing the B16 melanoma and a Beu melanic heterotransplant and the absence of images in the animals bearing the EMT6.

The scanning observations have also been carried out after the injection of B into the following mice:

C57 BL6 bearing the B16 melanoma

nu/nu SSCUP nudes bearing the Beu heterotransplant.

We have been able to observe very good tumoral definition from 3 to 17 h after injection into the animals bearing these two tumoral models.

This biological study shows that the derivatives according to the invention are useful markers of the melanoma:

their toxicity is relatively low

the autoradiograms give lasting constrasted images,

the comparison of the biodistribution in the C57 BL6 mice bearing the B16 melanoma is in favour of their use for imaging. In fact, at the site of the tumor, the percentages bound and the tissue/blood ratios are high up to the 8th hour after the injection.

The labelled compounds of the invention are thus particularly useful as radiopharmaceutical agents for diagnosing malignant melanomas, but will also be able to be used as agents for the treatment of these melanomas after labelling with ¹³¹ I.

Furthermore, the derivatives of formula I bearing stable isotopes such as ¹⁹ F or ¹³ C may be used for imaging in nuclear magnetic resonance (M.R.I.).

                                      TABLE 1                                      __________________________________________________________________________     C57 BL6 - B16                                                                          Time (h)                                                               Tissue  1       2       4       6       8       12     24                      __________________________________________________________________________     Blood   1,04 ± 0,094                                                                        0,74 ± 0,045                                                                        0,54 ± 0,070                                                                        0,21 ± 0,020                                                                        0,34 ± 0,024                                                                        0,09 ± 0,032                                                                       0,022 ± 0,0012       Plasma  0,82 ± 0,068                                                                        0,55 ± 0,027                                                                        0,45 ± 0,031                                                                        0,21 ± 0,022                                                                        0,38 ± 0,023                                                                        0,11 ± 0,043                                                                       0,024 ± 0,0015       Liver   6,04 ± 0,396                                                                        4,02 ± 0,217                                                                        2,46 ± 0,519                                                                        0,95 ± 0,081                                                                        0,80 ± 0,106                                                                        0,25 ± 0,028                                                                       0,16 ± 0,005         Spleen  5,91 ± 0,758                                                                        2,94 ± 0,517                                                                        1,36 ± 0,238                                                                        0,56 ± 0,162                                                                        0,46 ± 0,090                                                                        0,16 ± 0,075                                                                       0,02 ± 0,002         Pancreas                                                                               5,34 ± 0,412                                                                        3,42 ± 0,264                                                                        2,01 ± 0,432                                                                        0,55 ± 0,051                                                                        0,41 ± 0,091                                                                        0,13 ± 0,025                                                                        0,04 ± 0,0008       Kidney  8,56 ± 0,430                                                                        5,93 ± 0,583                                                                        3,67 ± 0,578                                                                        1,10 ± 0,087                                                                        0,84 ± 0,155                                                                        0,19 ± 0,038                                                                       0,07 ± 0,002         Intestine                                                                              5,22 ± 0,232                                                                        3,94 ± 0,318                                                                        2,80 ± 0,586                                                                        0,75 ± 0,128                                                                        0,71 ± 0,115                                                                        0,14 ± 0,032                                                                       0,02 ± 0,002         Stomach 6,03 ± 0,751                                                                        3,87 ± 0,853                                                                        2,35 ± 0,593                                                                        1,14 ± 0,252                                                                        1,65 ± 0,532                                                                        0,19 ± 0,048                                                                       0,07 ± 0,002         Lungs   10,99 ± 0,967                                                                       6,12 ± 0,424                                                                        4,29 ± 0,853                                                                        1,99 ± 0,410                                                                        1,11 ± 0,197                                                                        0,20 ± 0,084                                                                       0,05 ± 0,004         Eye     13,63 ± 1,053                                                                       12,98 ± 0,898                                                                       12,36 ± 0,903                                                                       12,13 ± 1,201                                                                       8,07 ± 0,294                                                                        8,49 ± 0,523                                                                       6,65 ± 0,282         Brain   2,67 ± 0,308                                                                        1,40 ± 0,074                                                                        0,70 ± 0,083                                                                        0,32 ± 0,032                                                                        0,18 ± 0,033                                                                        0,04 ± 0,011                                                                       0,005 ± 0,0006       Submaxillary                                                                           6,06 ± 0,772                                                                        3,60 ± 0,299                                                                        3,68 ± 1,320                                                                        1,12 ± 0,108                                                                        0,98 ± 0,152                                                                        0,44 ± 0,207                                                                       0,09 ± 0,012         glands                                                                         Muscle  1,55 ± 0,224                                                                        1,13 ± 0,064                                                                        0,66 ± 0,141                                                                        0,19 ± 0,021                                                                        0,14 ± 0,030                                                                        0,03 ± 0,007                                                                       0,009 ± 0,0004       Tumor   6,75 ± 0,671                                                                        6,04 ± 0,471                                                                        4,82 ± 1,191                                                                        3,53 ± 0,307                                                                        3,42 ± 0,367                                                                        1,01 ± 0,393                                                                       0,79                    __________________________________________________________________________                                                            ± 0,091               % ID/g                                                                   

                                      TABLE 2                                      __________________________________________________________________________     C57 BL6 - B16                                                                       Time (h)                                                                  Tissue                                                                              1       2       4       6       8       12       24                       __________________________________________________________________________     Plasma                                                                              0,77 ± 0,034                                                                        0,74 ± 0,016                                                                        0,83 ± 0,081                                                                        1,00 ± 0,034                                                                        1,13 ± 0,025                                                                        1,17 ± 0,059                                                                         1,12 ± 0,033          Liver                                                                               5,88 ± 0,402                                                                        5,44 ± 0,157                                                                        4,37 ± 0,397                                                                        4,62 ± 0,198                                                                        2,29 ± 0,212                                                                        3,67 ± 0,580                                                                         7,47 ± 0,510          Spleen                                                                              5,78 ± 0,804                                                                        3,91 ± 0,551                                                                        2,51 ± 0,437                                                                        2,83 ± 0,938                                                                        1,34 ± 0,266                                                                        2,36 ± 1,260                                                                         2,39 ± 1,127          Pancreas                                                                            5,30 ± 0,374                                                                        4,61 ± 0,166                                                                        3,55 ± 0,326                                                                        2,67 ± 0,180                                                                        1,21 ± 0,253                                                                        1,74 ± 0,183                                                                         1,88 ± 0,104          Kidney                                                                              8,78 ± 0,111                                                                        7,93 ± 0,317                                                                        6,69 ± 0,725                                                                        5,42 ± 0,542                                                                        2,43 ± 0,397                                                                        2,56 ± 0,364                                                                         3,12 ± 0,168          Intestine                                                                           5,13 ± 0,400                                                                        5,31 ± 0,281                                                                        4,96 ± 0,398                                                                        3,63 ± 0,431                                                                        2,15 ± 0,249                                                                        1,75 ±  0,347                                                                        1,11 ± 0,022          Stomach                                                                             5,82 ± 0,721                                                                        5,18 ± 1,168                                                                        4,12 ± 0,525                                                                        5,38 ± 0,931                                                                        4,81 ± 1,227                                                                        2,42 ± 0,360                                                                         3,07 ± 0,137          Lungs                                                                               10,69 ± 0,954                                                                       8,30 ± 0,479                                                                        7,55 ± 0,565                                                                        8,78 ± 1,068                                                                        3,20 ± 0,485                                                                        2,19 ± 0,117                                                                         2,37 ± 0,133          Eye  13,22 ± 0,776                                                                       17,51 ± 0,582                                                                       23,40 ± 1,943                                                                       59,48 ± 5,914                                                                       23,90 ± 1,899                                                                       129,62 ± 25,312                                                                      309,54 ± 22,214                                                             1                        Brain                                                                               2,54 ± 0,092                                                                        1,89 ± 0,020                                                                        1,28 ± 0,064                                                                        1,53 ± 0,063                                                                        0,52 ± 0,077                                                                        0,46 ± 0,045                                                                         0,25 ± 0,031          Sub- 5,92 ± 0,815                                                                        4,84 ± 0,237                                                                        6,16 ± 1,360                                                                        5,45 ± 0,282                                                                        2,83 ± 0,343                                                                        4,63 ± 0,745                                                                         4,26 ± 0,560          maxillary                                                                      glands                                                                         Muscle                                                                              1,46 ± 0,126                                                                        1,52 ± 0,030                                                                        1,17 ± 0,096                                                                        0,94 ± 0,078                                                                        0,40 ± 0,075                                                                        0,37 ± 0,033                                                                         0,38 ± 0,018          Tumor                                                                               6,56 ± 0,595                                                                        8,23 ± 0,684                                                                        8,57 ± 1,215                                                                        17,66 ± 2,170                                                                       10,34 ± 1,775                                                                       17,12 ± 9,505                                                                        37,4 ± 7,04           __________________________________________________________________________                                                           7                         ##STR8##                                                                 

                                      TABLE 3                                      __________________________________________________________________________     Swiss nu/nu SSCUP - Beu                                                        Time (h)                                                                       Tissue                                                                              1      2      4      6      8       12     24                             __________________________________________________________________________     Blood                                                                               0,87 ± 0,024                                                                       0,53 ± 0,056                                                                       0,32 ± 0,032                                                                       0,13 ± 0,021                                                                       0,05 ± 0,011                                                                        0,02 ± 0,003                                                                       0,01 ± 0,002                Plasma                                                                              0,46 ± 0,022                                                                       0,35 ± 0,057                                                                       0,20 ± 0,021                                                                       0,12 ± 0,034                                                                       0,04 ± 0,013                                                                        0,02 ± 0,002                                                                       0,01 ± 0,002                Liver                                                                               5,27 ± 0,220                                                                       3,50 ± 0,332                                                                       2,28 ± 0,164                                                                       0,94 ± 0,086                                                                       0,52 ± 0,042                                                                        0,28 ± 0,033                                                                       0,13 ± 0,019                Spleen                                                                              4,11 ± 0,217                                                                       2,12 ± 0,292                                                                       1,07 ± 0,023                                                                       0,28 ± 0,029                                                                       0,11 ± 0,015                                                                        0,04 ± 0,006                                                                       0,02 ± 0,002                Pancreas                                                                            3,99 ± 0,104                                                                       2,28 ± 0,270                                                                       1,39 ± 0,123                                                                       0,36 ± 0,039                                                                       0,12 ± 0,010                                                                        0,06 ± 0,011                                                                       0,05 ± 0,004                Kidney                                                                              7,63 ± 0,227                                                                       5,90 ± 0,691                                                                       4,28 ± 0,611                                                                       0,99 ± 0,140                                                                        0,28 ± 0,0029                                                                      0,10 ± 0,024                                                                       0,06 ± 0,016                Intestine                                                                           3,76 ± 0,348                                                                       2,35 ± 0,299                                                                       1,56 ± 0,204                                                                       0,52 ± 0,119                                                                       0,15 ± 0,020                                                                        0,08 ± 0,033                                                                       0,03 ± 0,009                Stomach                                                                             2,49 ± 0,074                                                                       1,51 ± 0,239                                                                       1,16 ± 0,123                                                                       0,49 ± 0,067                                                                       0,22 ± 0,025                                                                        0,07 ± 0,022                                                                       0,04 ± 0,006                Lungs                                                                               7,77 ± 0,172                                                                       4,71 ± 0,622                                                                       3,60 ± 0,272                                                                       1,25 ± 0,154                                                                       0,35 ± 0,058                                                                        0,08 ± 0,023                                                                       0,05 ± 0,009                Eye  0,64 ± 0,041                                                                       0,56 ± 0,135                                                                       0,34 ± 0,007                                                                       0,13 ± 0,009                                                                       0,07 ± 0,005                                                                        0,03 ± 0,002                                                                       0,03 ± 0,005                Brain                                                                               1,66 ± 0,103                                                                       1,13 ± 0,134                                                                       0,78 ± 0,054                                                                       0,28 ± 0,028                                                                       0,13 ± 0,019                                                                        0,01 ± 0,002                                                                       0,006 ± 0,0012              Sub- 5,11 ± 0,346                                                                       2,90 ± 0,275                                                                       1,71 ± 0,177                                                                       0,95 ± 0,255                                                                       0,24 ± 0,042                                                                        0,04 ± 0,007                                                                       0,03 ± 0,004                maxillary                                                                      glands                                                                         Muscle                                                                              1,30 ± 0,050                                                                       0,93 ± 0,144                                                                       0,51 ± 0,046                                                                       0,33 ± 0,063                                                                       0,08 ± 0,015                                                                        0,01 ± 0,002                                                                       0,01 ± 0,002                Tumor                                                                               3,51 ± 0,397                                                                       3,17 ± 0,405                                                                       3,25 ± 0,172                                                                       1,96 ± 0,241                                                                       1,07 ± 0,159                                                                        0,36 ± 0,050                                                                       0,07 ± 0,005                __________________________________________________________________________      % ID/g                                                                   

                                      TABLE 4                                      __________________________________________________________________________     Swiss nu/nu SSCUP - Beu                                                               Time (h)                                                                Tissue 1       2       4       6       8       12      24                      __________________________________________________________________________     Plasma  0,53 ± 0,022                                                                       0,66 ± 0,064                                                                        0,63 ± 0,010                                                                        0,95 ± 0,059                                                                        0,99 ± 0,047                                                                        1,06 ± 0,106                                                                        1,06 ± 0,169         Liver   6,07 ± 0,267                                                                       6,66 ± 0,297                                                                        7,37 ± 0,374                                                                        7,68 ± 1,136                                                                        11,47 ± 1,690                                                                       16,09 ± 1,576                                                                       10,48 ± 0,947        Spleen  4,72 ± 0,216                                                                       4,00 ± 0,352                                                                        3,58 ± 0,393                                                                        2,31 ± 0,394                                                                        2,45 ± 0,495                                                                        2,11 ± 0,121                                                                        2,01 ± 0,219         Pancreas                                                                               4,59 ± 0,098                                                                       4,28 ± 0,104                                                                        4,47 ± 0,222                                                                        2,97 ± 0,397                                                                        3,00 ± 0,585                                                                        3,10 ± 0,290                                                                        3,70 ± 0,447         Kidney  8,95 ± 0,306                                                                       11,17 ± 0,736                                                                       13,17 ± 0,980                                                                       6,62 ± 1,281                                                                        6,29 ± 1,071                                                                        5,52 ± 0,592                                                                        4,79 ± 0,428         Intestine                                                                              4,31 ± 0,363                                                                       4,52 ± 0,536                                                                        5,05 ± 0,576                                                                        3,57 ± 0,814                                                                        3,51 ± 0,709                                                                        4,00 ± 1,449                                                                        2,31 ± 0,291         Stomach 2,88 ± 0,170                                                                       2,84 ± 0,260                                                                        3,71 ± 0,252                                                                        3,75 ± 0,262                                                                        4,74 ± 0,687                                                                        3,44 ± 0,495                                                                        3,06 ± 0,265         Lungs   8,95 ± 0,152                                                                       8,75 ± 0,319                                                                        11,74 ± 1,029                                                                       8,76 ± 1,714                                                                        7,60 ± 1,088                                                                        4,06 ± 0,117                                                                        3,45 ± 0,151         Eye     0,74 ± 0,042                                                                       1,04 ± 0,178                                                                        1,13 ± 0,131                                                                        1,07 ± 0,117                                                                        1,69 ± 0,287                                                                        1,90 ± 0,300                                                                        2,38 ± 0,712         Brain   1,89 ± 0,094                                                                       2,13 ± 0,070                                                                        2,51 ± 0,173                                                                        1,87 ± 0,610                                                                        2,94 ± 0,644                                                                        0,94 ± 0,085                                                                        0,44 ± 0,034         Submaxillary                                                                           5,86 ± 0,297                                                                       5,53 ± 0,296                                                                        5,46 ± 0,282                                                                        6,73 ± 0,863                                                                        5,04 ± 0,504                                                                        2,33 ± 0,179                                                                        2,80 ± 0,207         glands                                                                         Muscle  1,50 ± 0,052                                                                       1,75 ± 0,141                                                                        1,65 ± 0,083                                                                        2,08 ± 0,315                                                                        1,78 ± 0,514                                                                        0,80 ± 0,089                                                                        0,91 ± 0,131         Tumor   4,08 ± 0,508                                                                       6,26 ± 0,947                                                                        9,70 ± 1,018                                                                        16,30 ± 4,185                                                                       24,43 ± 5,417                                                                       19,93 ± 2,180                                                                       6,41                    __________________________________________________________________________                                                            ± 2,022               ##STR9##                                                                       -                                                                        

                                      TABLE 5                                      __________________________________________________________________________     Swiss nu/nu SSCUP - Dau                                                               Time (h)                                                                Tissue 1      2      4      6      8      12     24                            __________________________________________________________________________     Blood  0,89 ± 0,054                                                                       0,52 ± 0,044                                                                       0,29 ± 0,025                                                                       0,23 ± 0,019                                                                       0,14 ± 0,042                                                                       0,06 ± 0,007                                                                       0,008 ± 0,0003             Plasma 0,55 ± 0,039                                                                       0,33 ± 0,035                                                                       0,24 ± 0,030                                                                       0,24 ± 0,025                                                                       0,15 ± 0,055                                                                       0,06 ± 0,006                                                                       0,007 ± 0,0005             Liver  5,68 ± 0,621                                                                       3,35 ± 0,262                                                                       2,10 ± 0,281                                                                       1,10 ± 0,045                                                                       0,71 ± 0,085                                                                        0,3 ± 0,015                                                                        0,1 ± 0,006               Spleen 3,48 ± 0,178                                                                       1,95 ± 0,097                                                                       0,80 ± 0,078                                                                       0,30 ± 0,023                                                                       0,16 ± 0,017                                                                       0,07 ± 0,006                                                                       0,02 ± 0,008               Pancreas                                                                              4,06 ± 0,208                                                                       2,29 ± 0,101                                                                       0,97 ± 0,108                                                                       0,41 ± 0,028                                                                       0,24 ± 0,024                                                                       0,13 ± 0,010                                                                       0,03 ± 0,004               Kidney 8,39 ± 0,908                                                                       5,12 ± 0,456                                                                       2,15 ± 0,296                                                                       0,78 ± 0,034                                                                       0,32 ± 0,059                                                                       0,14 ± 0,011                                                                       0,03 ± 0,004               Intestine                                                                             3,74 ± 0,340                                                                       2,67 ± 0,328                                                                       1,10 ± 0,174                                                                       0,42 ± 0,042                                                                       0,38 ± 0,101                                                                       0,27 ± 0,118                                                                       0,01 ± 0,002               Stomach                                                                               2,32 ± 0,172                                                                       1,85 ± 0,173                                                                       1,36 ± 0,349                                                                       1,17 ± 0,025                                                                       0,71 ± 0,182                                                                       0,38 ± 0,093                                                                       0,03 ± 0,004               Lungs  6,88 ± 0,840                                                                       5,63 ± 0,655                                                                       2,84 ± 0,393                                                                       0,76 ± 0,092                                                                       0,45 ± 0,082                                                                       0,11 ± 0,009                                                                       0,02 ± 0,004               Eye    0,68 ± 0,146                                                                       0,54 ± 0,897                                                                       0,31 ± 0,039                                                                       0,16 ± 0,010                                                                       0,10 ± 0,012                                                                       0,04 ± 0,004                                                                       0,02 ± 0,009               Brain  1,40 ± 0,114                                                                       0,99 ± 0,081                                                                       0,51 ± 0,060                                                                       0,20 ± 0,011                                                                       0,12 ± 0,008                                                                       0,02 ± 0.002                                                                       0,002 ± 0,0003             Submaxillary                                                                          4,75 ± 0,467                                                                       3,56 ± 0,280                                                                       1,50 ± 0,144                                                                       0,86 ± 0,124                                                                       0,77 ± 0,291                                                                       0,30 ± 0,040                                                                       0,02 ± 0,002               glands                                                                         Muscle 1,28 ± 0,092                                                                       0,79 ± 0,064                                                                       0,32 ± 0,035                                                                       0,11 ± 0,003                                                                       0,07 ± 0,011                                                                       0,02   0,006 ± 0,0005             Tumor  1,51 ± 0,074                                                                       1,29 ± 0,299                                                                       0,45 ± 0,033                                                                       0,23 ± 0,024                                                                       0,11 ± 0,031                                                                       0,07 ± 0,024                                                                       0,009 ± 0,0005             __________________________________________________________________________      % ID/g                                                                   

                                      TABLE 6                                      __________________________________________________________________________     Swiss nu/nu SSCUP - Dau                                                        Time (h)                                                                       Tissue                                                                              1      2       4      6      8      12      24                            __________________________________________________________________________     Plasma                                                                              0,62 ± 0,044                                                                       0,64 ± 0,038                                                                        0,82 ± 0,052                                                                       1,06 ± 0,019                                                                       1,07 ± 0,066                                                                       1,01 ± 0,077                                                                        0,97 ± 0,042               Liver                                                                               6,37 ± 0,593                                                                       6,47 ± 0,246                                                                        7,16 ± 0,528                                                                       4,91 ± 0,502                                                                       6,06 ± 1,210                                                                       5,19 ± 0,621                                                                        13,18 ± 1,199              Spleen                                                                              3,91 ± 0,051                                                                       3,83 ± 0,280                                                                        2,76 ± 0,205                                                                       1,37 ± 0,157                                                                       1,43 ± 0,375                                                                       1,22 ± 0,135                                                                        2,59 ± 1,002               Pancreas                                                                            4,56 ± 0,058                                                                       4,47 ± 0,250                                                                        3,64 ± 0,523                                                                       1,85 ± 0,189                                                                       2,06 ± 0,526                                                                       2,29 ± 0,215                                                                        3,82 ± 0,484               Kidney                                                                              9,13 ± 0,717                                                                       9,83 ± 0,360                                                                        7,46 ± 0,952                                                                       3,37 ± 0,421                                                                        2,9 ± 0,956                                                                       2,58 ± 0,433                                                                         4,6 ± 0,667               Intestine                                                                           4,23 ± 0,427                                                                       5,04 ± 0,290                                                                        3,75 ± 0,462                                                                       1,77 ± 0,237                                                                       2,93 ±  0,667                                                                      4,47 ± 1,625                                                                        1,52 ± 0,301               Stomach                                                                             2,63 ± 0,241                                                                       3,58 ± 0,209                                                                        4,50 ± 0,788                                                                       5,01 ± 0,598                                                                       5,16 ± 0,918                                                                        6,25 ± 0,1264                                                                      3,39 ± 0,540               Lungs                                                                               7,71 ± 0,767                                                                       10,92 ± 0,815                                                                       9,94 ± 1,404                                                                       3,34 ± 0,388                                                                       3,96 ± 0,961                                                                       1,84 ± 0,135                                                                        3,45 ± 0,597               Eye  0,74 ± 0,113                                                                       1,02 ± 0,127                                                                         1,1 ± 0,093                                                                       0,73 ± 0,033                                                                       0,78 ± 0,130                                                                       0,72 ± 0,033                                                                        2,99 ± 1,419               Brain                                                                               1,56 ± 0,065                                                                       1,91 ± 0,110                                                                        1,80 ± 0,209                                                                       0,91 ± 0,082                                                                       1,06 ± 0,278                                                                       0,44 ± 0,044                                                                        0,28 ± 0,039               Sub- 5,32 ± 0,379                                                                       6,97 ± 0,600                                                                        5,19 ± 0,382                                                                       3,70 ± 0,373                                                                       5,14 ± 0,541                                                                         21 ± 0,945                                                                        3,13 ± 0,281               maxillary                                                                      glands                                                                         Muscle                                                                              1,44 ± 0,087                                                                       1,53 ± 0,982                                                                        1,12 ± 0,110                                                                       0,49 ± 0,038                                                                       0,67 ± 0,181                                                                       0,36 ± 0,039                                                                        0,82 ± 0,064               Tumor                                                                               1,70 ± 0,036                                                                       2,47 ± 0,487                                                                        1,59 ± 0,140                                                                       0,98 ± 0,080                                                                       1,43 ± 0,329                                                                       1,36 ± 0,528                                                                        1,17 ± 0,108               __________________________________________________________________________      ##STR10##                                                                      -                                                                        

                  TABLE 7                                                          ______________________________________                                         C57 BL6 - B16                                                                            Time (h)                                                             % ID/g tissue                                                                              1         2      4      6    24                                    ______________________________________                                         Blood       1,31      0,67   0,27   0,14 0,03                                  Plasma      0,73      0,40   0,21   0,13 0,02                                  Liver       6,96      3,72   2,05   0,96 0,22                                  Kidney      14,37     8,64   4,42   1,86 0,16                                  Lungs       14,42     8,00   4,49   2,10 0,05                                  Eye         0,45      0,43   0,42   0,38 0,24                                  Brain       3,26      2,09   1,17   0,50 0,01                                  Muscle      2,55      1,33   0,67   0,20 0,02                                  Tumor       6,03      5,73   4,36   4,69 0,49                                  ______________________________________                                    

                  TABLE 8                                                          ______________________________________                                         C57 BL6 - B16                                                                  Tissue Time (h)                                                                Blood  1        2        4      6      24                                      ______________________________________                                         Plasma 0,56     0,60     0,79   0,90   0,77                                    Liver  5,32     5,55     7,58   6,80   7,49                                    Kidney 10,92    12,82    16,38  13,04  5,24                                    Lungs  11,00    11,94    16,64  14,66  1,74                                    Eye    9,70     17,50    39,70  73     200                                     Brain  2,48     3,11     4,33   3,51   0,46                                    Muscle 1,95     1,96     2,49   1,47   0,75                                    Tumor  4,70     8,51     16,17  36     16                                      ______________________________________                                    

                                      TABLE 9                                      __________________________________________________________________________     Swiss nu/nu SSCUP - Dau                                                        Time (h)                                                                       Tissue                                                                              1      2      4      6      8      12      24                             __________________________________________________________________________     Blood                                                                               0,89 ± 0,033                                                                       0,93 ± 0,099                                                                       0,30 ± 0,053                                                                       0,53 ± 0,083                                                                       0,11 ± 0,016                                                                       0,015 ± 0,0024                                                                      0,009 ± 0,0005              Plasma                                                                              0,71 ± 0,038                                                                       0,85 ± 0,15                                                                        0,28 ± 0,019                                                                       0,61 ± 0,047                                                                       0,13 ± 0,017                                                                       0,02 ± 0,002                                                                        0,009 ± 0,0008              Liver                                                                               4,95 ± 0,177                                                                       3,16 ± 0,39                                                                        1,52 ± 0,201                                                                       0,74 ± 0,054                                                                       0,63 ± 0,082                                                                       0,20 ± 0,013                                                                        0,19 ± 0,008                Spleen                                                                              2,54 ± 0,114                                                                       2,02 ± 0,17                                                                        0,62 ± 0,135                                                                       0,33 ± 0,030                                                                       0,14 ± 0,022                                                                       0,05 ± 0,005                                                                        0,09 ± 0,009                Pancreas                                                                            2,86 ± 0,127                                                                       2,13 ± 0,17                                                                        0,83 ± 0,185                                                                       0,40 ± 0,026                                                                       0,14 ± 0,034                                                                       0,08 ± 0,005                                                                        0,01                           Kidney                                                                              8,15 ± 0,499                                                                       6,17 ± 0,46                                                                        2,51 ± 0,589                                                                       1,07 ± 0,164                                                                       0,42 ± 0,144                                                                       0,08 ± 0,005                                                                        0,04 ± 0,002                Intestine                                                                           3,10 ± 0,314                                                                       2,57 ± 0,16                                                                        1,19 ± 0,218                                                                       1,05 ± 0,120                                                                       0,36 ± 0,057                                                                       0,05 ± 0,006                                                                         0,01 ± 0,0004              Stomach                                                                             2,38 ± 0,154                                                                       3,03 ± 0,547                                                                       1,23 ± 0,201                                                                         2 ± 0,253                                                                        0,58 ± 0,098                                                                       0,10 ± 0,009                                                                        0,02 ± 0,002                Lungs                                                                               5,35 ± 0,319                                                                       5,56 ± 0,598                                                                       2,63 ± 0,485                                                                       0,93 ± 0,038                                                                       0,43 ± 0,143                                                                       0,04 ± 0,004                                                                        0,02 ± 0,002                Eye  0,51 ± 0,028                                                                       0,50 ± 0,024                                                                       0,21 ± 0,021                                                                       0,19 ± 0,012                                                                       0,06 ± 0,012                                                                       0,01 ± 0,002                                                                        0,008 ± 0,0010              Brain                                                                               1,28 ± 0,079                                                                       1,25 ± 0,142                                                                       0,63 ± 0,101                                                                       0,22 ± 0,020                                                                       0,14 ± 0,035                                                                       0,01 ± 0,002                                                                        0,002 ± 0,0002              Sub- 4,28 ± 0,207                                                                       4,14 ± 0,370                                                                       1,68 ± 0,351                                                                       2,74 ± 0,492                                                                       0,39 ± 0,046                                                                       0,04 ± 0,005                                                                        0,02 ± 0,002                maxillary                                                                      glands                                                                         Muscle                                                                              1,04 ± 0,040                                                                       6,86 ± 0,101                                                                       0,41 ± 0,120                                                                       0,12 ± 0,026                                                                       0,07 ± 0,014                                                                       0,008 ± 0,0013                                                                      0,002 ± 0,0002              Tumor                                                                               1,19 ± 0,048                                                                       1,27 ± 0,086                                                                       0,93 ± 0,425                                                                       0,34 ± 0,020                                                                       0,12 ± 0,024                                                                       0,02    0,007 ± 0,0006              __________________________________________________________________________      % ID/g                                                                   

                                      TABLE 10                                     __________________________________________________________________________     Swiss nu/nu SSCUP - Dau                                                        Time (h)                                                                       Tissue                                                                              1      2      4      6      8      12      24                             __________________________________________________________________________     Plasma                                                                              0,80 ± 0,017                                                                       0,89 ± 0,068                                                                       0,94 ± 0,058                                                                       1,16 ± 0,016                                                                       0,19 ± 0,020                                                                       0,16 ± 0,037                                                                        1,07 ± 0,154                Liver                                                                               5,56 ± 0,225                                                                       3,62 ± 0,68                                                                        5,21 ± 0,519                                                                       1,43 ± 0,439                                                                       6,03 ± 0,678                                                                       13,34 ± 0,462                                                                       21,88 ± 1,493               Spleen                                                                              2,84 ± 0,091                                                                       2,31 ± 0,36                                                                        2,07 ± 0,256                                                                       0,62 ± 0,045                                                                       1,28 ± 0,158                                                                       3,68 ± 0,493                                                                        11,17 ± 1,75                Pancreas                                                                            3,20 ± 0,099                                                                       2,42 ± 0,36                                                                        2,70 ± 0,300                                                                       0,76 ± 0,050                                                                       1,22 ± 0,151                                                                         5 ± 0,310                                                                         1,40 ± 0,120                Kidney                                                                              9,10 ± 0,286                                                                       7,00 ± 1,03                                                                        8,03 ± 0,813                                                                       2,01 ± 0,252                                                                       3,72 ± 0,573                                                                       5,46 ± 0,217                                                                        4,64 ± 0,328                Intestine                                                                           3,44 ± 0,231                                                                       2,87 ± 0,34                                                                        4,08 ± 0,599                                                                       1,97 ± 0,112                                                                       3,30 ± 0,269                                                                       3,20 ± 0,502                                                                        1,16 ± 0,141                Stomach                                                                             2,66 ± 0,101                                                                       3,40 ± 0,694                                                                       4,34 ± 0,924                                                                       3,78 ± 0,400                                                                       5,35 ± 0,355                                                                       7,03 ± 0,728                                                                        2,28 ± 0,165                Lungs                                                                                 6 ± 0,353                                                                        6,33 ± 1,166                                                                       8,77 ± 0,838                                                                       1,82 ± 0,187                                                                       3,69 ± 0,585                                                                       3,04 ± 0,401                                                                        1,72 ± 0,182                Eye  0,57 ± 0,011                                                                       0,55 ± 0,052                                                                       0,71 ± 0,056                                                                       0,36 ± 0,023                                                                       0,60 ± 0,040                                                                       0,88 ± 0,081                                                                        0,94 ± 0,213                Brain                                                                               1,44 ± 0,069                                                                       1,43 ± 0,261                                                                       2,21 ± 0,304                                                                       0,44 ± 0,060                                                                       1,31 ± 0,180                                                                       0,74 ± 0,072                                                                        0,22 ± 0,029                Sub- 4,82 ± 0,285                                                                       4,48 ± 0,220                                                                       5,44 ± 0,297                                                                       5,16 ± 0,853                                                                       3,65 ± 0,266                                                                       2,52 ± 0,236                                                                        1,81 ± 0,169                maxillary                                                                      glands                                                                         Muscle                                                                              1,17 ± 0,040                                                                       0,98 ± 0,182                                                                       1,24 ± 0,153                                                                       0,24 ± 0,056                                                                       0,74 ± 0,216                                                                       0,45 ± 0,111                                                                        0,27 ± 0,043                Tumor                                                                               1,33 ± 0,015                                                                       1,39 ± 0,103                                                                       2,68 ± 0,757                                                                       0,65 ± 0,025                                                                       1,17 ± 0,314                                                                       1,11 ± 0,059                                                                        0,79 ± 0,092                __________________________________________________________________________      ##STR11##                                                                 

We claim:
 1. A compound of formula ##STR12## wherein Y₁ represents a CO group,I* represents ¹²⁵ I, ¹²³ I, ¹³¹ I R₁ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl, and R₂ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl.
 2. A compound according to claim 1, which is ##STR13## *I being ¹²⁵ I, ¹²³ I or ¹³¹ I. 